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Creatine Supplementation in Exercise, Sport, and Medicine Richard B Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 DOI 10.1186/s12970-017-0173-z REVIEW Open Access International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine Richard B. Kreider1*, Douglas S. Kalman2, Jose Antonio3, Tim N. Ziegenfuss4, Robert Wildman5, Rick Collins6, Darren G. Candow7, Susan M. Kleiner8, Anthony L. Almada9 and Hector L. Lopez4,10 Abstract Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson’s, Huntington’s disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly. Moreover, significant health benefits may be provided by ensuring habitual low dietary creatine ingestion (e.g., 3 g/day) throughout the lifespan. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN). Keywords: Ergogenic aids, Performance enhancement, Sport nutrition, Athletes, Muscular strength, Muscle power, Clinical applications, Safety, Children, Adolescents Background concussion and/or spinal cord neuroprotection. A number Creatine is one of the most popular nutritional ergogenic of clinical applications of creatine supplementation have aids for athletes. Studies have consistently shown that also been studied involving neurodegenerative diseases creatine supplementation increases intramuscular creatine (e.g., muscular dystrophy, Parkinson’s, Huntington’s concentrations, can improve exercise performance, and/or disease), diabetes, osteoarthritis, fibromyalgia, aging, brain improve training adaptations. Research has indicated that and heart ischemia, adolescent depression, and pregnancy. creatine supplementation may enhance post-exercise recov- The purpose of this review is to provide an update to the ery, injury prevention, thermoregulation, rehabilitation, and current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to * Correspondence: [email protected] update the position stand of International Society of Sports 1Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department Nutrition (ISSN) related to creatine supplementation. of Health & Kinesiology, Texas A&M University, College Station, TX 77843-4243, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 2 of 18 Metabolic role reported to have lower intramuscular creatine stores (90– Creatine, a member of the guanidine phosphagen family, is 110 mmol/kg of dry muscle) and therefore may observe a naturally occurring non-protein amino acid compound greater gains in muscle creatine content from creatine found primarily in red meat and seafood [1–4]. The major- supplementation [11, 13, 20, 21]. Conversely, larger ath- ity of creatine is found in skeletal muscle (~95%) with small letes engaged in intense training may need to consume 5– amounts also found in the brain and testes (~5%) [5, 6]. 10 g/day of creatine to maintain optimal or capacity whole About two thirds of intramuscular creatine is phosphocrea- body creatine stores [22] and clinical populations may tine (PCr) with the remaining being free creatine. The total need to consume 10–30 g/day throughout their lifespan creatine pool (PCr + Cr) in the muscle averages about to offset creatine synthesis deficiencies and/or provide 120 mmol/kg of dry muscle mass for a 70 kg individual [7]. therapeutic benefit in various disease states [13, 19, 23]. However, the upper limit of creatine storage appears to be Phosphagens are prevalent in all species and play an im- about 160 mmol/kg of dry muscle mass in most individuals portant role in maintaining energy availability [1, 2, 24, 25]. [7, 8]. About 1–2% of intramuscular creatine is degraded Theprimarymetabolicroleofcreatineistocombinewith into creatinine (metabolic byproduct) and excreted in the a phosphoryl group (Pi) to form PCr through the enzym- urine [7, 9, 10]. Therefore, the body needs to replenish atic reaction of creatine kinase (CK). Wallimann and col- about 1–3 g of creatine per day to maintain normal leagues [26–28] suggested that the pleiotropic effects of Cr (unsupplemented) creatine stores depending on muscle are mostly related to the functions of CK and PCr (i.e., mass. About half of the daily need for creatine is obtained CK/PCr system). As adenosine triphosphate (ATP) is de- from the diet [11]. For example, a pound of uncooked beef graded into adenosine diphosphate (ADP) and Pi to pro- and salmon provides about 1–2 g of creatine [9]. The vide free energy for metabolic activity, the free energy remaining amount of creatine is synthesized primarily in released from the hydrolysis of PCr into Cr + Pi can be the liver and kidneys from arginine and glycine by the used as a buffer to resynthesize ATP [24, 25]. This helps enzyme arginine:glycine amidinotransferase (AGAT) to maintain ATP availability particularly during maximal ef- guanidinoacetate (GAA), which is then methylated by fort anaerobic sprint-type exercise. The CK/PCr system guanidinoacetate N-methyltransferase (GAMT) using also plays an important role in shuttling intracellular en- S-adenosyl methionine to form creatine (see Fig. 1) [12]. ergy from the mitochondria into the cytosol (see Fig. 2). Some individuals have been found to have creatine The CK/PCr energy shuttle connects sites of ATP produc- synthesis deficiencies due to inborn errors in AGAT, tion (glycolysis and mitochondrial oxidative phosphoryl- GMAT and/or creatine transporter (CRTR) deficiencies ation) with subcellular sites of ATP utilization (ATPases) and therefore must depend on dietary creatine intake in [24, 25, 27]. In this regard, creatine enters the cytosol order to maintain normal muscle and brain concentra- through a CRTR [16, 29–31]. In the cytosol, creatine and tions of PCr and Cr [13–19]. Vegetarians have been associated cytosolic and glycolytic CK isoforms help Fig. 1 Chemical structure and biochemical pathway for creatine synthesis. From Kreider and Jung [6] Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 3 of 18 Fig. 2 Proposed creatine kinase/phosphocreatine (CK/PCr) energy shuttle. CRT = creatine transporter; ANT = adenine nucleotide translocator; ATP = adenine triphosphate; ADP = adenine diphosphate; OP = oxidative phosphorylation; mtCK = mitochondrial creatine kinase; G = glycolysis; CK-g = creatine kinase associated with glycolytic enzymes; CK-c = cytosolic creatine kinase; CK-a = creatine kinase associated with subcellular sites of ATP utilization; 1 – 4 sites of CK/ATP interaction. From Kreider and Jung [6] Fig. 3 Role of mitochondrial creatine kinase (mtCK) in high energy metabolite transport and cellular respiration. VDAC = voltage-dependent anion channel; ROS = reactive oxygen species; RNS = reactive nitrogen species; ANT = adenine nucleotide translocator; ATP = adenine triphosphate; ADP = adenine diphosphate; Cr = creatine; and, PCr = phosphocreatine. From Kreider and Jung [6] Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 4 of 18 maintain glycolytic ATP levels, the cytosolic ATP/ADP ra- and protein have been reported to more consistently promote tio, and cytosolic ATP-consumption [27]. Additionally, cre- greater creatine retention [8, 22, 49, 50]. An alternative atine diffuses into the mitochondria and couples with ATP supplementation protocol is
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